Association of Genetic Variation in TCF7L2, SLC22A1 and KCNJ11 Genes with Risk for Type 2 Diabetes in Bangladeshi Population

Abstract

Type 2 diabetes mellitus (T2DM) is a multifactorial disease. Its prevalence has been rapidly increasing throughout the world, which is associated with several gene polymorphisms including KCNJ11, TCF7L2, SLC22A1 etc. The aims of this study were designated to investigate the association of KCNJ11 (rs5219), TCF7L2 (rs12255372) and SLC22A1 (rs628031) gene polymorphisms with T2DM in population of Bangladesh. In a case-control study with 697 unrelated subjects, 326 healthy controls and 371 diabetic patients (diagnosed based on American Diabetes Association criteria) were recruited for this study. The serum fasting glucose, lipid profiles, creatinine, alanine amino transferase (ALT), HbA1C and serum insulin level were measured by standard methods. HOMA B%, HOMA S% and HOMA IR were calculated by HOMA-SIGMA software version 2.2. QUICKI and Secretory HOMA were calculated by standard formula. Chemical method was used for DNA extraction from whole blood sample. PCR-RFLP method was used to detect KCNJ11 E23K (with Ban II), TCF7L2 (with Nla III) and SLC22A1 gene polymorphism (with MSc I) by restriction enzyme digestion. Data were analyzed using independent t-test, Chi-square or Fisher exact test, as appropriate. p<0.05 was considered significant. Baseline data showed that FBG and HbA1c% level of diabetic group was significantly higher than control group (p<0.001). HOMAB% (p<0.001); HOMA S% (p<0.001), QUICKY (p<0.001) and secretory HOMA (p<0.005) were significantly lower; whereas insulin resistance was significantly higher (p<0.001) in diabetic subjects compared to control respectively. The TG and LDL levels were significantly higher (p<0.001) in diabetes group compare to control group respectively. Statistically significant associations exist among E23K, K23K and E23K+K23K variants of KCNJ11 gene with T2DM where the E23E genotype was considered as reference group; and K allele of cases were significantly higher than E allele (p<0.005). E23K variant has high risk for predisposition of diabetes in both male and female respectively. The frequency of E23K variant was significantly higher in diabetic subjects with positive family history of diabetes compared to without family history; and also showed a diabetic risk factor for semi urban and urban population than rural subjects. No association was found among genotypes with diabetogenic parameters.

TCF7L2 genome analysis was revealed a significant association of TT and GT+TT variants in diabetic group, when the GG genotype was considered as reference group. TT variants have high risk for predisposition of diabetes in male than female; and with positive family history of diabetes than without family history. GT and TT variants were shown a significant association with semi urban and urban diabetic subjects than rural. In relation to diabetogenic parameters, a significant increase of QUICKY was found in TT variants in diabetic group (p<0.05) compared to GG and GT genotype. Whereas, HOMA IR (p<0.05) and QUICKY (0<0.001) were significantly higher in GT+TT variants than GG variant respectively. The risk for T2DM was also calculated in relation to SLC22A1 gene. There was significant relationship exist among GA, AA and GA+AA variants when GG genotype was considered as reference group respectively. Polymorphic “A” allele frequency was significant (p<0.005) higher in diabetic group than control. The incidence of diabetes was significantly higher in both male and female subjects in diabetic as well as in control group with or without family history of diabetes. Highly significant associations of GA and AA variants were found with both semi urban and urban diabetic subjects than that of rural diabetic subjects. Although significant differences were not found in clinical parameters according to genotypic variants. The genetic linkage analysis of selective genes (KCNJ11/TCF7L2/SLC22A1) suggested that polymorphism of EK/TT/GA, EK/TT/AA and KK/TT/GA alleles showed the higher risk in T2DM subjects. From the obtained results, it can be concluded that KCNJ11, TCF7L2 and SLC22A1 gene polymorphisms are strongly associated with T2DM in population of Bangladesh.